The present invention is directed to novel heteroaryl-naphthalenyl-alkylamines, their salts, processes for their preparation, and compositions comprising them. The novel compounds of this invention are useful in inhibiting the cytochrome P450RAI enzyme (Cyp26) in animals, including humans, for the treatment and/or prevention of various diseases and conditions that respond to treatment by retinoids and by naturally occurring retinoic acid.
Retinoic acid, retinoid-like compounds, and pharmaceutical compositions comprising retinoic acid or rectinoid-like compounds as the active ingredient are known in the art to play a significant role in the regulation and differentiation of epithelial cells. Such regulatory and differentiating effects, which include the ability to promote cell differentiation, apoptosis, and the inhibition of cell proliferation, make retinoic acid and retinoid compounds useful agents in tumor therapy and in treating such conditions as skin-related diseases. Retinoids and retinoid compounds are known as agents for treating skin-related diseases such as actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses, keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus; for preventing, treating, and reversal of glucocorticoid, age, and photo damage to the skin. Retinoids and retinoid compounds are also known as topical anti-microbial and skin antipigmentation agents. Retinoids, with their ability to serve as differentiating agents, redirect cells towards their normal phenotype and therefore may reverse or suppress developing malignant lesions or prevent cancer invasions altogether. Therefore, retinoid compounds are useful for the prevention and treatment of cancerous and precancerous conditions, including, for example, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, colon, bladder, cervix, uterus, stomach, lung, esophagus, blood and lymphatic system, larynx, oral cavity, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes, and in the treatment of Kaposi's sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, for example, proliferative vitreoretinopathy, retinal detachment, corneopathies such as dry eye, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulation tissue plasminogen activator. Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil®, diseases associated with the immune systems, including use of the present compounds as immunosuppresant and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. Retinoid compounds have also been discovered to be useful in treating type II non-insulin dependent diabetes mellitus (NIDDM).
Several compounds having retinoid-like activity are marketed under appropriate regulatory approvals in the United States of America and elsewhere as medicants for the treatment of several diseases responsive to treatment with retinoids. Retinoic acid (RA) itself is a naturally occurring retinoid, the biologically most active metabolite of vitamin A, is biosynthesized and present in a multitude of human and mammalian tissues and is known to play a crucial role in the regulation of gene expression, cellular differentiation, proliferation of epithelial cells, and other important biological processes in mammals including humans.
Retinoids have demonstrated reversal of malignant growth in vivo and in vitro and are effective as chemopreventive agents. Retinoids could successfully be used to treat oral leukoplakia, a potentially premalignant mucosal lesion, and the occurrence of second primary tumors following head and neck squamous cell carcinoma (HNSCC) could be inhibited or delayed. These second primary tumors, which occur at an incidence rate of 2-3% per year, are a major cause of death after surgical resection of early-stage head and neck cancer. Retinoid therapy has also been explored in the treatment of glioma tumors, primary and metastatic melanoma cells, and has shown anti-metastatic activities in rat invasive prostate adenocarcinoma cells. Retinoid leukemia therapy works through terminal differentiation and the eventual apoptotic death of leukemic cells and has been shown to result in complete remission in up to 90% of patients with Acute Promyelocytic Leukemia (APL).
Although treatment with retinoids is highly successful in inducing complete remission in APL, if maintained on retinoids alone, most patients will relapse within a few months. The clinical use of retinoic acid in the treatment of cancer has been significantly hampered by the prompt emergence of resistance, which is believed to be caused by increased retinoic acid metabolism. Retinoic acid is metabolized by Cyp26A1 (Cyp26), an inducible cytochrome P450 enzyme, that inactivates RA by oxidation of RA to 4-HO-atRA, 8-HO-atRA, and 4-oxo-atRA. The tightly controlled negative feedback mechanism limits the availability of RA and thereby limits its biological activity. Compounds have been identified that inhibit Cyp26 and therefore RA metabolism and have shown to enhance the antiproliferative effects of RA and cause an increase in endogenous levels of RA in plasma and in tissues.
Cyp26 inhibitors, also known as retinoic acid metabolism-blocking agents (RAMBAs), are known and include, for example, Liarozole (Liazal™) and R116010. Such Cyp26 inhibitors have demonstrated therapeutic benefits in dermatological and cancerous conditions in vitro, in vivo, and in clinical settings. In several preclinical tumor models, Liarozole displayed antitumoral properties which correlated with decreased endogenous retinoic acid metabolism and therefore, an increase in RA accumulation within tumor cells. In cancer patients, Liarozole has been shown to increase the half-life of orally administered RA and 13-cis-RA. Unfortunately, one of the limitations of Liarozole and many Cyp26 inhibitors described in the literature was their lack of specificity. Liarozole as well as other Cyp26 inhibitors inhibit other cytochrome P450-mediated reactions and are limited due to their lack of specificity towards other cytochrome P450 enzymes. This lack of specificity might explain the limited risk benefit ratio (the activity/toxicity ratio was considered insufficient by the FDA) observed in prostate cancer patients in the Liarozole phase III clinical trials. Therefore, there is clearly a need within retinoid therapy for Cyp26 inhibitors (RAMBA's) that are highly potent and selective that have greater selectivity to other cytochrome P450 enzymes, fewer side effects, and favorable drug-like properties including sufficient water solubility, bioavailability, sufficient pharmacokinetic properties, extraction ratios, and limited toxicity to balance the activity/toxicity ratio and for use in the treatment of various dermatological and cancerous conditions.
The present invention shows highly potent and selective novel heteroaryl-naphthalenyl-alkylamines Cyp26 inhibitors that provide therapeutic benefits in the treatment or prevention of the diseases and conditions which respond to treatment by retinoids or are controlled by natural retinoic acid. The perceived mode of action of these compounds is that by inhibiting the Cyp26 enzyme (CP450RAI [cytochrome P450 retinoic acid inducible]) that has been proven in the art to catabolyze natural retinoic acid, endogenous retinoic acid level is elevated to a level where desired therapeutic benefits are attained. The endogenous levels of all natural and synthetic retinoids which are metabolized by Cyp26 would be expected to increase from inhibition of Cyp26 by the novel heteroaryl-naphthalenyl-alkylamines Cyp26 inhibitors described in this invention. Co-administration with a composition of the natural or synthetic retinoids with the compounds, or pharmaceutically acceptable salts thereof, disclosed in this invention can increase the level of retinoids. The co-administration of the natural and synthetic retinoids, which are catabolized by Cyp26, with at least one compound disclosed in this invention is a method for treating skin-related or cancerous diseases to yield higher endogenous levels of the retinoids. The compounds of this invention are active at nanomolar concentrations and selectively and potently inhibit enzymes involved in retinoic acid catabolism and therefore result in the effective modulation of desirable levels of atRA.
The following publications describe or relate to the role of Cyp26 inhibitors and their ability to slow the catabolism of retinoic acid, thereby increasing endogenous retinoic acid levels, and their potential for the treatment of dermatological diseases and cancers:
Altucci, L. et. al. “Retinoic Acid-induced Apoptosis in Leukemia Cells is Mediated by Paracrine Action of Tumor-Selective Death Ligand Trail”, Nature Med. 2001, 7, 680-686;
Altucci, L.; Gronemeyer, H. “The Promise of Retinoids to Fight Against Cancer”, Nature Reviews (Cancer), 2001, 1, 181-193;
Winum, J. Y.; et. al. “Synthesis of New Targretin® Analogues that Induce Apoptosis in Leukemia HL-60 Cells”, Bioorganic & Medicinal Chemistry Letters, 2002, 12, 3529-3532.
Kuijpers, et. al. “The Effects of Oral Liarozole on Epidermal Proliferation and Differentiation in Severe Plaque Psoriasis are Comparable with Those of Acitretin”, British Journal of Dermatology, 1998. 139, 380-389;
Van Wauwe, et. al. “Liarozole, an Inhibitor of Retinoic Acid Metabolism, Exerts Retinoid-Mimetic Effects in Vivo”, The Journal of Pharmacology and Experimental Therapeutics, 1992, 261, 773-779.
Haque, M.; Andreola, F.; DeLuca, L. M. “The Cloning and Characterization of a Novel Cytochrome P450 Family, Cyp26, with Specificity towards Retinoic Acid”, Nutri Rev. 1999, 56, 84-85.
Wouters, W. et. al. “Effects of Liarozole, a New Antitumoral Compound and Retinoic Acid-Induced Inhibition of Cell Growth and on Retinoic Acid Metabolism in MCF-7 Breast Cancer Cells”, Cancer Res, 1992, 52, 2841-2846;
Freyne, E. et. al. “Synthesis of Liazal™, a Retinoic Acid Metabolism Blocking Agents (RAMBA) with Potential Clinical Applications in Oncology and Dermatology”, Bioorganic & Medicinal Chemistry Letters, 1998, 8, 267-272;
Miller, W. H. “The Emerging Role of Retinoids and Retinoic Acid Metabolism Blocking Agents in the Treatment of Cancer”, Cancer, 1998, 83, 1471-1482;
Van Heusden J. et. al. “Inhibition of all-TRANS-retinoic Acid Metabolism by R116010 Induces Antitumor Activity”, Br. J. Cancer, 2002, 86(4), 605-611;
Debruyne, F. J. M. et. al. “Liarozole-A Novel Treatment Approach for Advanced Prostate Cancer: Results of a Large Randomized Trial versus Cyproterone”, Urology, 1998, 52, 72-81;
De Coster, R. et. al. “Experimental Studies with Liarozole (R75251): An Antitumor Agent which Inhibits Retinoic Acid Breakdown”, J. Steroid Biochem. Molec. Biol. 1992, 43, 197-201;
Njar, V. C. O.; Brodie, A. M. H. “Inhibitors of Cytochrome P450 Enzymes: Their Role in Prostate Cancer Therapy”, I Drugs, 1999, 1, 495-506;
Miller, V. A.; Rigas, J. R.; Muindi, J. F. R.; Tong, W. P.; Venkatraman, E.; Kris, M. G.; Warrell Jr. R. P. “Modulation of all-trans-retinoic acid pharmacokinetics by liarozole”, Cancer Chemother. Pharmacol. 1994, 34, 522-526;
Muindi, J.; Frankel, S. R.; Miller Jr. W. H.; Jakubowski, A.; Scheinberg, D. A.; Young, C. W.; Dmitrovski, E.; Warrell, Jr. R. P. “Continuous treatment with all-trans-retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid ‘resistance’ in patients with acute promyelocytic leukemia”, Blood. 1992, 79, 299-303;
Muindi, J F.; Scher, H. I.; Rigas, J. R.; Warrell Jr. R. P.; Young, C. W. “Elevated plasma lipid peroxide content correlates with rapid plasma clearance of all-trans-retinoic acid in patients with advanced cancer”, Cancer Res. 1994, 54, 2125-2128.
U.S. Pat. No. 6,303,785B1 describes inhibitors of cytochrome P450RAI. International Patent Publication No. WO 99/29674 describes inhibitors of retinoic acid metabolism. International Patent Publication No. WO 01/30762A1 describes imidazol-4-ylmethanols used as inhibitors of steroid C17-20 Lyase.
U.S. Pat. Nos. 6,291,677 and 6,124,330 and International Patent Publication No. WO 02/03912 A2 describe inhibitors of cytochrome P450RAI. International Application No. PCT/US00/11833 describes PPAR agonists or antagonists. International Patent Publication No. WO 02/06281 describes selective β3 adrenergic receptor agonists. International Patent Publication No. WO 01/068647 describes an antiviral agent. International Patent Publication No. WO 01/062234 describes a farnesyl protein transferase inhibitor. International Patent Publication No. WO 01/055155 describes compounds which have antibacterial activities. International Patent Publication No. WO 01/044170 describes adamantine derivatives. International Patent Publication No. WO 01/000615 describes benzimidazoles. International Patent Publication No. WO 00/069843 describes compounds for the treatment of inflammations. International Patent Publication No. WO 00/043384 describes aromatic heterocyclic ureas as anti-inflammatory agents. Japanese Patent Publication No. JP 01/43635 describes benzimidazole compositions and derivatives. International Patent Publication No. WO 99/40092 describes GABAa agonists, antagonists or inverse agonists. International Patent Publication No. WO 99/376609 describes virucides used against cytomegalovirus. German Patent Publication No. DE 75/6388 describes substituted 2-aryl-4-amino-quinazolines. International Patent Publication No. WO 98/54168 describes 2-oxoimidazole derivatives. International Patent Publication No. WO 98/23593 describes inhibitors of apolipoprotein B and/or microsomal triglyceride transfer protein. U.S. Pat. No. 5,852,213 describes matrix metalloproteinase inhibitors of the MMP enzyme. U.S. Pat. No. 5,834,483 and International Patent Publication No. WO 97/37665 describes endothelin antagonists. International Patent Publication No. WO 97/24117 describes substituted hydroxamic acid compounds. International Patent Publication No. WO 95/29689 describes N-carboxyalkyl derivatives. U.S. Pat. No. 5,461,162 describes N-acyl auxilliary compounds. European Patent Publication No. 611,776 describes pseudopeptides with antiviral activity. European Patent Publication No. 569,220 describes organic sulfonamides. European Patent Publication No. 545,376 describes guanidinothiazoles. German Patent No. DE 4,201,435 describes trifluoromethyl ketones. German Patent No. DE 4,138,820 describes compounds used as herbicides. International Patent Publication No. WO 91/19717 describes phosphodiesterase inhibitors. European Patent Publication No. EP 437,729 describes peptide retroviral protease inhibitors. European Patent Publication No. EP 412,350 describes peptides as renin inhibitors. International Patent Publication No. WO 89/10919 describes carbostyril derivatives. International Patent Publication No. WO 00/064888 describes diaryl carboxylic acids and derivatives. WO 99/47497 describes naphthyl and indolyl acylsulfonamides. German Patent No. DE 4304650 describes benzimidazoles, xanthines, and analogs. International Patent Application No. PCT/CA99/00212 describes compounds used for treating or preventing prostaglandin mediated diseases.